1. Field of the Invention
This invention relates to pharmaceutical compositions for application to the skin and to a method for the treatment of proliferative skin diseases. More particularly, this invention relates to topical compositions containing an oxygenated cholesterol, e.g. 26-hydroxycholesterol, or a pharmaceutically acceptable derivative of an oxygenated cholesterol, e.g. an ester or an ether. This invention relates, particularly, to a topical composition containing 26-hydroxycholesterol or cholest-1,4-diene-26-ol-3-one or a pharmaceutically acceptable derivative thereof and an agent for enhancing the penetration of these compounds into and through the skin.
2. Prior Art
Proliferative skin diseases are widespread throughout the world and afflict millions of humans and their domesticated animals. This invention provides a method for the treatment of such diseases and pharmaceutical compositions useful in alleviating such diseases.
As used herein, the expression "proliferative skin diseases" means benign skin diseases which are characterized by epidermal cell proliferation, or division, and may also be associated with incomplete tissue differentiation. Psoriasis is the most serious of the skin diseases with which this invention is concerned. Such diseases include: psoriasis, atopic dermatitis, nonspecific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant sun induced keratosis, non-malignant keratosis, and seborrheic dermatitis in humans and atopic dermatitis and mange in domesticated animals.
Heretofore, proliferative skin diseases have been generally accepted by mankind as an ongoing evil having degrees of severity variable with time, with inherited skin traits and external factors, but always have been recognized as unsightly, painful, morbid diseases. Over the history of mankind, innumerable medicines and treatments have been proposed, tried and used with varying degrees of success. However, no treatment heretofore devised or pharmaceutical compositions used has been entirely successful in the wide spectrum of specific diseases encompassed by the expression proliferative skin diseases.
The present day treatments of commercial significance which are prescribed and used for the treatment of proliferative skin diseases and associated inflammation include three approaches: (1) topical applications: coal tar derivatives, 5-fluorouracil, vitamin A acid, glucocorticoids in high dosage, bath oils and non-specific emolient creams and ointments; (2) systemic administration: glucocorticoids and classic anti-cancer agents, for example, methothrexate, hydroxyurea, azaibine, cyclophosphamide; and (3) physical modalities: ultraviolet light, irradiation, and in severe cases, surgery.
Numerous compositions are known for the treatment of skin disorders and diseases by topical application which provide, in certain cases, some remission of the original symptoms, each treatment suffers some defect, for example, temporary and incomplete mitigation of symptoms, rapid re-occurrence of the disease when mitigation is terminated, serious and sometimes irreversible damage (atrophy) resulting from the topical application for extended times of glucocorticoids, acute bone marrow suppression and cirrhosis of the liver resulting from the protracted use of methothrexate which may lead to death of the patient, and the causation of cancer by the application of anti-cancer drugs, irradiation, or ultraviolet rays.
Psoriasis is perhaps the most prevalent type proliferative skin disease. The early stage eruption of psoriasis may be non-specific in appearance and in such early stages is often confused with a variety of other skin diseases. The initial lesion is an erythematous papule which may progress to pustulation. Soon after the erythematous papules, the characteristic papulosquamous plaque appears. The typical psoriatic eruption consists of erythematous, scaling plaques of variable size. The lesions are, in most cases, symmetrical. Clinically, the scale is distinctive, silvery and luxuriant in its pristine, untreated state. Underneath is a dull red surface which, upon removal of the scale, may show fine capillary bleeding points. Always sharply limited in border and frequently clearing in the center, psoriasis may come in any size and the scale may, in turn, range from being absent to extremely thick.
Psoriasis, in addition to being an inflammatory disease, is a benign hyperplastic disease of the skin. Epidermal cells in areas of skin involvement have a very rapid rate of replication. The mitotic index of the germinative cell population per unit length of involved epidermis is increased, and there is a reduced epidermal cell transmit time, or epidermal cell "turnover" time in involved areas. Accordingly, the epidermis of the psoriatic lesion grows very fast (about ten times normal rates) and sheds large amounts of scale. This is one of the key factors in the pathology of the disease.
In view of the foregoing, the principal thrust of the treatment protocol for psoriasis centers around use of antimetabolites or nicotinamide antagonists, such as the topical application of methotrexate, and folic acid antagonist; Azaribine, an orotidylate decarboxylase inhibitor (triacetyl-6-azauridine); hydroxyurea; 6-aminonicotinamide; and systemically with mycophenolic acid. The first three drugs are antimetabolic agents and have been reported effective in producing remissions in patients with severe recalcitrant disease.
However, all of these drugs have major side effects and can be given only in very severe cases and under extremely careful supervision by those experienced in their use. In many instances, some of the adverse effects of these drugs are worse than the psoriasis, particularly when using antineoplastic agents.
In view of the foregoing, what is needed is a method for treating psoriasis by the topical application of a suitable compound to the psoriatic lesion. It would further be highly desirable to have a composition which is not only useful in the topical treatment of psoriasis, but other type proliferative diseases, preferably by antimetabolites which characteristically inhibit mitosis.
26-Hydroxycholesterol, some of its derivatives and analogs, certain properties and some uses thereof are known, for example:
Van Lier et al, Biochemistry 6, 3269 (1967) and Aringer et al. Biochem. Biophys. Acta., 665, 13 (1981) describes the finding that 26-hydroxycholesterol present in human atheromata in vivo is of enzymatic origin.
Kandutsch et al, Science 201, 498 (1978) reported that oxygenated sterols such as 25-hydroxycholesterol inhibit cholesterol synthesis in vitro.
Javitt et al, "26-Hydroxycholesterol Identification and Quantitation in Human Serum", J. Biol. Chem., 256:12644 (1981) describes the presence of 26-hydroxycholesterol (cholest-5-ene-3 beta, 26-diol) in biological fluids after neonatal life.
Javitt et al, in J. Biol. Chem., 256:12644 (1981) describes the determination of 26-hydroxycholesterol in biological fluids by GLC-MS analysis using a deuterated analog. See, also, Javitt et al, Biomedical Mass Spectrometry, 9:61-63 (1982).
U.S. Pat. No. 4,427,668 to Javitt (1984) describes a process for regulating cholesterol level in the body, particularly of tissue cholesterol, through the monitoring and/or administration of 26-hydroxycholesterol. Administration is through the use of injectables, such as intravenous injectables, utilizing conventional pharmaceutical carriers for such use in tablet, capsule, oral liquids or parenteral injectables. See also Japanese No. 58 172317 to Javitt et al which describes the use of 26-hydroxycholesterol compositions for depression of hyperplasia in smooth muscle cell.
None of these foregoing references, however, teach or suggest the use of 26-hydroxycholesterol for the topical treatment of skin disorders or diseases.
Nor does any of these references disclose a method for passing 26 hydroxycholesterol through the skin directly into the blood stream without requiring an injection through the skin.
It is therefore an object of this invention to provide a new composition and method for treating proliferative skin diseases.
Another object of the invention is to provide a method for treating proliferative skin diseases by topical application of a therapeutic composition to the effected skin area.
It is still another object of this invention to provide novel pharmaceutically acceptable compositions including an oxygenated cholesterol e.g. 26-hydroxycholesterol, or a pharmaceutically effective derivative thereof.
It is yet another object of this invention to provide cosmetic as well as therapeutic compositions containing 26-hydroxycholesterol, or its derivatives which, when topically applied, will substantially alleviate the symptoms of various inflammatory skin disorders.
It is yet another object of this invention to provide compositions for transdermal delivery of an oxygenated cholesterol to a subject.